For over 30 years, 8-methoxypsoralen in combination with sunlight or UV-A radiation (320 - 400 nm) has been used as a pigment stimulating agent in the treatment of vitiligo, a disease of pigmentary disorder. Recently, oral psoralen photochemotherapy (PUVA) has been found to be very effective in the treatment of psoriasis and other skin diseases. While these treatments have proved to be highly successful and relatively harmless for a short-term period of 1 to 3 years, there is an understandable concern with respect to the possible long-term effects. Because of the nature of the psoralen plus UV-A interaction with epidermal and dermal cell DNA and the fact that high doses of ultraviolet radiation can cause cataracts, actinic elastosis or aging of the skin, and skin cancer, it is essential that these risks be considered in the long-term treatment of patients with chronic skin diseases. In establishing the long-term safety and effectiveness of psoralens and high-intensity ultraviolet radiation, the basic and clinical research investigations that were initiated under this project include: (1) the absorption, excretion and metabolism of 8-methoxypsoralen (8-MOP) and 4,5',8-trimethylpsoralen (TMeP); (2) the identification and characterization of the metabolites of 8-MOP and TMeP; (3) the induction of the hepatic microsomal enzymes known as mixed-function oxidases (MFO) and cytochrome P-450 psoralens; (4) the comparison of the MFO-enzyme induction effects with phenobarbital and 3-methylcholanthrene, the known inducers of these enzyme activities; (5) the photoreactivity of different psoralens with DNA, and the nature of the photochemical reactions of different psoralens with skin DNA; (6) the examination of the relationship between the photosensitizing activity of certain psoralens, their cross-linking ability with DNA, and their therapeutic effectiveness; (7) the studies of mast cell mediators in patients with solar urticaria that are usually sensitive to sunlight; (8) the control of melanin hyperpigmentation stimulated by sunlight in patients with melasma by examining the depigmenting potency of various phenolic and nonphenolic chemical agents.